SPECIFIC AIMS The production of new neurons within the adult dentate gyrus represents a novel form of hippocampal plasticity associated with certain forms of hippocampal-dependent learning. Our recent studies suggest that the production of new granule neurons within the adult dentate gyrus is impaired in mice exposed to moderate ethanol throughout gestation. While several studies have demonstrated robust effects of acute ethanol on neurogenesis in the adult hippocampus and in isolated stem cells in culture (Crews and Nixon, 2003;He et al., 2005;Nixon and Crews, 2004), our studies were the first to demonstrate that fetal alcohol exposure (FAE) results in persistent deficits in adult hippocampal neurogenesis in mice (Choi et al., 2005). Interestingly, these neurogenic deficits only become apparent when the adult FAE mouse is behaviorally challenged. For example, when exposed for several weeks to enriched living conditions, control mice display a 2-fold increase in hippocampal neurogenesis, whereas FAE mice respond with no increase in the neurogenic response. Because we found no difference in the size of the progenitor pool in the dentate subgranular zone, nor any change in the rate of progenitor proliferation, our studies suggest impaired survival and integration of new neurons within the adult dentate under conditions of enriched environment. Currently, our studies are focused on understanding the mechanistic underpinnings of this impaired neurogenic response in FAE mice. Our overarching hypothesis is that the impaired neurogenic response to enriched environment is due to an intrinsic defect in the adult neural stem cells themselves and/or due to microenvironmental changes that persist within the neurogenic niche. To test this hypothesis, we propose the following Specific Aims: Specific Aim 1: Does FAE result in intrinsic defects in adult neural stem cells? To address this question, we will compare the self-renewal and differentiation properties of neural stem cells isolated from adult FAE vs. control mice in vitro. Specific Aim 2: Does FAE result in microenvironmental perturbations that persist within the neurogenic niche of the adult hippocampus? To address this question we will compare the vascular density and microglial properties within the adult subgranular zone/dentate hilus region in FAE vs. control mice, since these components regulate, in part, the neurogenic response to enriched environment.